PURPOSE: Colorectal cancer is the second leading cause of cancer-related death in the United States. A multi-omics approach has contributed in identifying various cancer-specific mutations, epigenetic alterations, and cells response to chemotherapy. This study aimed to determine the factors associated with colorectal cancer survival and develop and validate a polygenic survival scoring system (PSS) using a multi-omics approach. PATIENTS AND METHODS: Data were obtained from the Cancer Genome Atlas (TCGA). Colon Adenocarcinoma (TCGA-COAD) data were used to develop a survival prediction model and PSS, whereas rectal adenocarcinoma (TCGA-READ) data were used to validate the PSS. Cox proportional hazards regression analysis was conducted to examine the association between the demographic characteristics, clinical variables, and mRNA gene expression. RESULTS: Overall accuracy of PSS was also evaluated. The median overall survival for TCGA-COAD patients was 7 years and for TCGA-READ patients was 5 years. The multivariate Cox proportional hazards model identified age, cancer stage, and expression of nine genes as predictors of colon cancer survival. Based on the median PSS of 0.38, 48% of TCGA-COAD patients had high mortality risk. Patients in the low risk group had significantly higher 5-year survival rates than those in the high group (p <0.0001). The PSS demonstrated a high overall accuracy in predicting colorectal cancer survival. CONCLUSION: This study integrated clinical and transcriptome data to identify survival predictors in patients with colorectal cancer. PSS is an accurate and valid measure for estimating colorectal cancer survival. Thus, it can serve as an important tool for future colorectal cancer research.